Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.
Laboratory of Molecular and Cellular Neuroscience, the Rockefeller University, New York, NY 10065.
eNeuro. 2018 Nov 8;5(5). doi: 10.1523/ENEURO.0332-18.2018. eCollection 2018 Sep-Oct.
A recent study showed that p11 expressed in cholinergic interneurons (CINs) of the nucleus accumbens (NAc) is a key regulator of depression-like behaviors. Dopaminergic neurons projecting to the NAc are responsible for reward-related behaviors, and their function is impaired in depression. The present study investigated the role of p11 in NAc CINs in dopamine responses to rewarding stimuli. The extracellular dopamine and acetylcholine (ACh) levels in the NAc were determined in freely moving male mice using microdialysis. Rewarding stimuli (cocaine, palatable food, and female mouse encounter) induced an increase in dopamine efflux in the NAc of wild-type (WT) mice. The dopamine responses were attenuated (cocaine) or abolished (food and female mouse encounter) in constitutive p11 knock-out (KO) mice. The dopamine response to cocaine was accompanied by an increase in ACh NAc efflux, whereas the attenuated dopamine response to cocaine in p11 KO mice was restored by activation of nicotinic or muscarinic ACh receptors in the NAc. Dopamine responses to rewarding stimuli and ACh release in the NAc were attenuated in mice with deletion of p11 from cholinergic neurons (ChAT-p11 cKO mice), whereas gene delivery of p11 to CINs restored the dopamine responses. Furthermore, chemogenetic studies revealed that p11 is required for activation of CINs in response to rewarding stimuli. Thus, p11 in NAc CINs plays a critical role in activating these neurons to mediate dopamine responses to rewarding stimuli. The dysregulation of mesolimbic dopamine system by dysfunction of p11 in NAc CINs may be involved in pathogenesis of depressive states.
最近的一项研究表明，在伏隔核（NAc）的胆碱能中间神经元（CINs）中表达的 p11 是抑郁样行为的关键调节因子。投射到 NAc 的多巴胺能神经元负责与奖励相关的行为，而它们的功能在抑郁症中受损。本研究探讨了 NAc CINs 中 p11 在多巴胺对奖励刺激反应中的作用。使用微透析技术在自由活动的雄性小鼠中测定 NAc 中的细胞外多巴胺和乙酰胆碱（ACh）水平。奖励刺激（可卡因、美味食物和雌性小鼠遭遇）诱导野生型（WT）小鼠 NAc 中多巴胺外排增加。在组成型 p11 敲除（KO）小鼠中，多巴胺反应减弱（可卡因）或消除（食物和雌性小鼠遭遇）。可卡因引起的多巴胺反应伴随着 NAc 中 ACh 外排的增加，而 p11 KO 小鼠中可卡因引起的多巴胺反应减弱可通过 NAc 中烟碱或毒蕈碱 ACh 受体的激活得到恢复。在从胆碱能神经元（ChAT-p11 cKO 小鼠）中缺失 p11 的小鼠中，对奖励刺激的多巴胺反应和 NAc 中 ACh 释放减弱，而向 CINs 中传递 p11 则恢复了多巴胺反应。此外，化学遗传学研究表明，p11 是 CIN 对奖励刺激产生反应所必需的。因此，NAc CINs 中的 p11 在激活这些神经元以介导对奖励刺激的多巴胺反应中起关键作用。NAc CINs 中 p11 功能障碍导致中边缘多巴胺系统失调可能与抑郁状态的发病机制有关。
